Submissions for variant NM_001035.3(RYR2):c.7925G>A (p.Arg2642Lys)

gnomAD frequency: 0.00034  dbSNP: rs377473366

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721138	SCV000235149	likely benign	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Invitae	RCV002517796	SCV000285748	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617307	SCV000736705	likely benign	Cardiovascular phenotype	2021-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182764	SCV001338641	likely benign	not specified	2020-04-13	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.7925G>A (p.Arg2642Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249184 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 44- fold the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.7925G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as likely benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001188652	SCV001355743	likely benign	Cardiomyopathy	2019-01-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917692	SCV004742619	likely benign	RYR2-related condition	2022-11-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).